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Dr. B. Levin is Professor Emeritus, The University of Texas MD Anderson Cancer Center, Houston, TX.
Dr. Lieberman is Chief, Division of Gastroenterology, Oregon Health and Science University, Portland Veterans Medical Center, Portland, OR.
Dr. McFarland is Adjunct Professor of Radiology, Washington University; St. Luke's Hospital and Center for Diagnostic Imaging, Chesterfield, MO.
Dr. Smith is Director, Cancer Screening, Cancer Control Science Department, American Cancer Society, Atlanta, GA.
Dr. Brooks is Director, Prostate and Colorectal Cancer, Cancer Control Science Department, American Cancer Society, Atlanta, GA.
Ms. Andrews is Research Associate, Cancer Control Science Department, American Cancer Society, Atlanta, GA.
Dr. Dash is Doctoral Candidate, Department of Epidemiology, Emory University, Rollins School of Public Health, Atlanta, GA.
Dr. Giardiello is John G. Rangos Sr. Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Dr. Glick is Clinical Professor of Radiology, University of Pennsylvania Health System, Philadelphia, PA.
Dr. T. Levin is Staff Physician, Gastroenterology Department, Kaiser Permanente Walnut Creek Medical Center, Walnut Creek, CA.
Dr. Pickhardt is Associate Professor, Radiology Department, University of Wisconsin Hospital and Clinics, Madison, WI.
Dr. Rex is Professor of Medicine, Indiana University, Indianapolis, IN.
Dr. Thorson is Associate Professor of Surgery; and Program Director, Section of Colon and Rectal Surgery, Creighton University School of Medicine; and Clinical Associate Professor of Surgery, University of Nebraska College of Medicine, Omaha, NE.
Dr. Winawer is Attending Physician, Memorial Sloan-Kettering Cancer Center, New York, NY.
Disclosures: Workgroup members were asked to disclose relationships, including potential financial conflicts of interest. The following was disclosed: D. Lieberman served on the scientific advisory board for Exact Sciences, ending September 30, 2007. B. McFarland receives honoraria for serving on the medical advisory boards for Vital Images and Medicsight. P. Pickhardt serves as a paid consultant to Covidien, Viatronix, Fleet, Medicsight, and Philips. D. Rex receives an honorarium for serving as a speaker and research support for serving as an investigator for Olympus; serves on the scientific advisory board and receives research support for serving as an investigator for Given Imaging; and serves on the scientific advisory boards for Avantis, NeoGuide, G.I. View, and American BioOptics. M. Rodriguez-Bigas is on the speakers bureau of Genzyme. R. Wender serves on the scientific advisory boards for Epigenomics, GeneNews, and G.I. View, but receives no personal income for doing so. D. Johnson serves as an Exact Sciences clinical investigator, but has received no support since 2006. C. D. Johnson and Mayo Clinic have licensed a CT colonography software patent to GE Medical Systems.
Published online through CA First Look at http://CAonline.AmCancer.Soc.org.
To earn free CME credit for successfully completing the online quiz based on this article, go to http://CME.AmCancerSoc.org.
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ABSTRACT |
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INTRODUCTION |
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The goal of cancer screening is to reduce mortality through a reduction in incidence of advanced disease. To this end, modern CRC screening can achieve this goal through the detection of early-stage adenocarcinomas and the detection and removal of adenomatous polyps, the latter generally accepted as nonobligate precursor lesions. Adenomatous polyps are common in adults over age 50 years, but the majority of polyps will not develop into adenocarcinoma; histology and size determine their clinical importance.10,11 The most common and clinically important polyps are adenomatous polyps, which represent approximately one-half to two-thirds of all colorectal polyps and are associated with a higher risk of CRC. Thus, most CRC screening studies evaluate the detection rate of invasive CRC, as well as advanced adenomas, which conventionally are defined as polyps greater than or equal to 10 mm or histologically having high-grade dysplasia or significant villous components. The evidence for the importance of colorectal polyps in the development of CRC is largely indirect, but nonetheless extensive and convincing, and has been described in detail.11–13
Today there is a range of options for CRC screening in the average-risk population, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy (FSIG), colonoscopy, double-contrast barium enema (DCBE), and computed tomographic colonography (CTC). Stool tests are best suited for the detection of cancer, although they also will deliver positive findings for some advanced adenomas, while the structural exams can achieve the dual goals of detecting adenocarcinoma as well as identifying adenomatous polyps.14 These tests may be used alone or in combination to improve sensitivity or, in some instances, to ensure a complete examination of the colon if the initial test cannot be completed. Although screening tests for CRC vary in terms of the degree of supporting evidence, potential efficacy for incidence and mortality reduction, cost-effectiveness, and acceptability, any one of these options applied in a systematic program of regular screening has the potential to significantly reduce deaths from CRC.
Beginning in 1980, the American Cancer Society (ACS) first issued formal guidelines for CRC screening in average-risk adults.15 Since then, the ACS has periodically updated its CRC guidelines,16–19 including adding recommendations for high-risk individuals in 1997.17 Other organizations also have issued recommendations for CRC screening, most notably the US Preventive Services Task Force,20,21 the American College of Radiology (ACR),22,23 and the US Multi-Society Task Force on Colorectal Cancer (USMSTF).12,24 Recently, the ACS and the USMSTF collaborated on an update of earlier recommendations for postpolypectomy and post-CRC resection surveillance in response to reports suggesting significant deviation from existing recommendations.25,26 Since 1997, the organizational guidelines for average-risk adults have grown increasingly similar and represent a broad organizational consensus on the value, options, and methods for periodic screening for CRC.
In the last decade, there has been an increase in the number of technologies available for CRC screening, and in the case of stool tests, there has been growth in the number of commercial versions of guaiac-based and immunochemical-based stool tests (gFOBT and FIT). This growth in options also has been accompanied by changing patterns in the proportion of adults using different tests, with FSIG rates declining, colonoscopy rates increasing, use of stool blood tests remaining somewhat constant, and use of the DCBE for screening now becoming very uncommon.8
There are pros and cons to having a range of options for CRC screening. Despite the fact that the primary barriers to screening are lack of health insurance, lack of physician recommendation, and lack of awareness of the importance of CRC screening,27 the historical evidence shows that adults have different preferences and patterns of use among the available CRC screening tests.28–31 Although population preferences or resistance to a particular technology may change over time or may be influenced by referring physicians, it also may be true that over time some adults may persist in choosing one technology and rejecting another. Furthermore, at this time not all options are available to the entire population, and transportation, distance, and financial barriers to some screening technologies may endure for some time. Although in principle all adults should have access to the full range of options for CRC screening, the fact that simpler, lower-cost options are available in most settings, whereas other more costly options are not universally available, is a public health advantage. However, for average-risk adults, multiple testing options challenge the referring physician to support an office policy that can manage a broad range of testing choices, their follow-up requirements, and shared decision making related to the options. Shared decision making for multiple screening choices is both demanding and time consuming and is complicated by the different characteristics of the tests and the test-specific requirements for individuals undergoing screening.31 In addition, the description of benefits is complicated by different performance characteristics of the variants of the occult blood tests and uncertain differences between test performance in research settings and test performance in clinical practice. These challenges have been discussed in the past,19,32 and they still are with us today.
In this guideline review, we have reassessed the individual test evidence and comparative evidence for stool tests, including gFOBT, FIT, and stool DNA test (sDNA), and the structural exams, including FSIG, colonoscopy, DCBE, and CTC, the latter also known as virtual colonoscopy. We have sought to address a number of concerns about the complexity of offering multiple screening options and the degree to which the range of screening options and their performance, costs, and demands on individuals poses a significant challenge for shared decisions. An overriding goal of this update is to provide a practical guideline for physicians to assist with informed decision making related to CRC screening. These guidelines are for individuals at average risk. Individuals with a personal or family history of CRC or adenomas, inflammatory bowel disease, or high-risk genetic syndromes should continue to follow the most recent recommendations for individuals at increased or high risk.24–26
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GUIDELINES DEVELOPMENT, METHODS, AND FRAMEWORK |
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While there is clear experimental evidence that screening for CRC with gFOBT is associated with reduced incidence and mortality from CRC screening,5,6,33 most of the information supporting the use of the other colorectal screening tests is based on observational and inferential evidence. In this review, priority was placed on studies of asymptomatic average-risk or higher-risk populations that were followed by testing with colonoscopy in all or nearly all study participants as a validation measure.
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SUMMARY OF THE RECOMMENDATIONS |
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Individuals and health care professionals should also understand that screening tests for CRC broadly fall into 2 categories. In one category are the fecal tests (ie, gFOBT, FIT, and sDNA), which are tests that primarily are effective at identifying CRC. Some premalignant adenomatous polyps may be detected, providing an opportunity for polypectomy and the prevention of CRC, but the opportunity for prevention is both limited and incidental and is not the primary goal of CRC screening with these tests. In the second category are the partial or full structural exams (ie, FSIG, colonoscopy, DCBE, and CTC),44 which are tests that are effective at detecting cancer and premalignant adenomatous polyps. These tests differ in complexity and accuracy for the detection of CRC and advanced neoplasia. When performed properly, each of these structural exams has met the standard of detecting at least half of prevalent or incident cancers at the time of testing.
It is the strong opinion of this expert panel that colon cancer prevention should be the primary goal of CRC screening. Tests that are designed to detect both early cancer and adenomatous polyps should be encouraged if resources are available and patients are willing to undergo an invasive test. These tests include the partial or full structural exams mentioned above. These tests require bowel preparation and an office or hospital visit and have various levels of risk to patients. These tests also have limitations, greater patient requirements for successful completion, and potential harms. Significant positive findings on FSIG, DCBE, and CTC require follow-up colonoscopy.
The panel recognized that some patients will not want to undergo an invasive test that requires a bowel preparation, may prefer to have screening in the privacy of their home, or may not have access to the invasive tests due to lack of coverage or local resources. Collection of fecal samples for blood or DNA testing can be performed at home, without bowel preparation. However, providers and patients should understand the following limitations and requirements of noninvasive tests:
If patients are not willing to have repeated testing or have colonoscopy if the test is abnormal, these programs will not be effective and should not be recommended.
Based on our review of the historic and recent evidence, the tests in Table 1 are acceptable options for the early detection of CRC and adenomatous polyps for asymptomatic adults aged 50 years and older (also see Table 2).
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SCREENING TESTS FOR THE DETECTION OF CRC |
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gFOBT
gFOBT are the most common stool blood tests in use for CRC screening and the only CRC screening tests for which there is evidence of efficacy from prospective, randomized controlled trials. Guaiac-based tests detect blood in the stool through the pseudoperoxidase activity of heme or hemoglobin, while immunochemical-based tests react to human globin. The usual gFOBT protocol consists of collecting 2 samples from each of 3 consecutive bowel movements at home. Prior to testing with a sensitive guaiac-based test, individuals usually will be instructed to avoid aspirin and other nonsteroidal anti-inflammatory drugs, vitamin C, red meat, poultry, fish, and some raw vegetables because of diet-test interactions that can increase the risk of both false-positive and false-negative (specifically, vitamin C) results.46 Collection of all 3 samples is important because test sensitivity improves with each additional stool sample.14
gFOBT—Efficacy and Test Performance. Three large, prospective, randomized controlled trials with gFOBT have demonstrated that screened patients have cancers detected at an early and more curable stage than unscreened patients. Over time (8 to 13 years), each of the trials demonstrated significant reductions in CRC mortality of 15% to 33%.5,6,34 Moreover, incidence reduction of 20% was demonstrated in one trial (Minnesota) after 18 years of follow up, which has been attributed to relatively higher rates of colonoscopy in the study (38% of subjects in the screened group).7
The sensitivity and specificity of a gFOBT has been shown to be highly variable and varies based on the brand or variant of the test47; specimen collection technique38; number of samples collected per test14; whether or not the stool specimen is rehydrated (ie, adding a drop of water to the slide window before processing)48; and variations in interpretation, screening interval, and other factors.46
The reported sensitivity of a single gFOBT varies considerably. In a review by Allison and colleagues, sensitivity for cancer ranged from 37.1% for unrehydrated Hemoccult II to 79.4% for Hemoccult SENSA.47 Lieberman and Weiss compared one-time testing with rehydrated Hemoccult II and observed 35.6% sensitivity for cancer.14 In a study comparing gFOBT (unrehydrated Hemoccult II) with sDNA, sensitivity for cancer was only 12.9%.37 More recently, Allison and colleagues compared a high-sensitivity gFOBT (Hemoccult SENSA) with an FIT and observed 64.3% sensitivity for cancer and 41.3% for advanced adenomas.49 Thus, the data reveal a range of performance among gFOBT variants that allows them to be grouped into low- and high-test sensitivity groups. The specificity of gFOBT also is variable, with low-test sensitivity gFOBT (such as Hemoccult II) tending to have very high specificity and high-test sensitivity gFOBT (such as Hemoccult SENSA) having lower specificity. In a comparison of various stool blood tests, Allison and colleagues observed specificity for cancer and advanced adenomas of 97.7% and 98.1%, respectively, for Hemoccult II, with a combined specificity for cancer and advanced adenomas of 98.1%. For Hemoccult SENSA, which had greater sensitivity for cancer and advanced adenomas compared with Hemoccult II, specificity for cancer and advanced adenomas was 86.7% and 87.5%, respectively, with a combined specificity for cancer and advanced adenomas of 87.5%.47
A significant limitation of the potential of testing with gFOBT is that it is commonly performed in the doctor's office as a single-panel test following a digital rectal exam.39 In a recent national survey of primary care physicians, 31.2% reported using only the in-office method of gFOBT, and an additional 41.2% of physicians reporting using both the in-office method or the take-home method. While this approach may seem pragmatic, Collins et al demonstrated that sensitivity is only 4.9% for advanced neoplasia and only 9% for cancer.38 The accuracy of this method is so low that it cannot, under any circumstances or rationale of convenience, be endorsed as a method of CRC screening.
An additional limitation observed in the current use of gFOBT is inadequate follow up of a positive test. Despite the fact that all existing CRC screening guidelines recommend colonoscopy follow up of a positive gFOBT, in the same survey that revealed high rates of in-office gFOBT, nearly one-third of physicians reported that they followed up a positive gFOBT with a repeat gFOBT, and a substantial percentage reported that they referred patients to sigmoidoscopy rather than colonoscopy after a positive gFOBT. Similar patterns of testing and responses to positive test results have been reported by patients undergoing at-home screening.39
gFOBT—Benefits, Limitations, and Harms. Annual testing with gFOBT has been shown to reduce both CRC mortality and incidence. Testing for occult blood is simple and is associated with minimal harms, although any testing with gFOBT is associated with a possibility of a positive test result that will require follow up with colonoscopy, which is associated with a greater risk of harms. The limitation of gFOBT is that many of the individual tests have limited test sensitivity under the best of circumstances, and this sensitivity may be further compromised by poor and incomplete specimen collection and inadequate or improper processing and interpretation. Program sensitivity (ie, the outcome of repeat annual testing) is considerably higher, but the systems to ensure regular, annual testing often are not in place to support either the patient or his or her physician to be adherent. Further, testing in the office following a digital rectal exam, which is highly inaccurate, has been common and still may persist at significant levels today. When either the test, the testing procedure, or both have very low test sensitivity and when positive tests are not followed up with colonoscopy, the potential is high for patients to have a false sense of reassurance after testing. Finally, patients who choose gFOBT for CRC screening must understand that annual testing is required.
Quality Assurance. If patients and their providers select gFOBT for CRC screening, they should be aware of several quality issues based on programmatic performance in clinical trials. First, the test must be performed properly with 3 stool samples obtained at home. A single-stool sample FOBT collected after digital rectal exam in the office is not an acceptable screening test, and it is not recommended. Prior to testing with a sensitive guaiac-based test, individuals should be instructed to avoid nonsteroidal anti-inflammatory drugs such as ibuprofen, naproxen, or aspirin (more than one adult aspirin per day) for 7 days prior to testing unless they are on a cardioprotective regimen. There has been debate as to whether additional dietary restrictions reduce compliance with testing and are necessary to reduce the risk of both false-negative and false-positive results. Results of a meta-analysis that examined completion and positivity results found little support for the influence of dietary restrictions on completion or positivity rates, with the exception of completion rates in one study that imposed severe restrictions. However, manufacturers still endorse avoidance of vitamin C in excess of 250 mg from either supplements or citrus fruits and juices and avoidance of red meats (beef, lamb, and liver) for 3 days before testing. This seems prudent since recent consumption of red meat is associated with increased false positivity, and excess vitamin C can result in false-negative results. Second, it is critically important that physician offices and laboratories follow recommended quality-assurance procedures for test development and interpretation. Although rehydration of gFOBT slides increases sensitivity, it is not recommended because it can adversely affect the readability of the test and also substantially increases the false-positive rate. Sinatra and colleagues observed considerable variation in the interpretation of gFOBT among 13 laboratories in Melbourne, Australia, and concluded that ongoing technician training and review of laboratory procedures were important.50 Better results may be achieved if guaiac-based tests are routinely processed and interpreted in a clinical laboratory. Third, if the test is positive, patients should be advised to have colonoscopy. Repeating the stool test or follow up with noncolonoscopy tests are inappropriate. Fourth, if the test is negative, patients should understand that they need to have repeated testing annually.
gFOBT—Conclusions and Recommendations. Annual screening with high-sensitivity gFOBT (such as Hemoccult SENSA) that have been shown in the published, peer-reviewed literature to detect a majority of prevalent CRC in an asymptomatic population is an acceptable option for colorectal screening in average-risk adults aged 50 years and older. Any positive test should be followed up with colonoscopy. Individuals should be informed that annual testing is necessary to achieve the fullest potential of this test and that they will need follow-up colonoscopy if test results are positive. Screening for CRC with gFOBT in the office following digital rectal exam or as part of a pelvic examination is not recommended and should not be done. Commonly used guaiac tests, with or without rehydration, that have not been shown in the literature to detect a majority of prevalent CRC at the time of testing are no longer recommended.
FIT
The concept of applying an immunochemical method to testing stool for occult blood was first proposed in the 1970s,51 and commercialization of the technology began in the 1980s. The use of FIT in the United States has lagged behind some other countries, mostly due to the higher costs associated with FIT compared with gFOBT. However, recently increased reimbursement by Medicare made the use of FIT financially viable and has led to its wider acceptability in the United States.52
FIT has several technological advantages when compared with gFOBT. FIT detects human globin, a protein that along with heme constitutes human hemoglobin. Thus, FIT is more specific for human blood than guaiac-based tests, which rely on detection of peroxidase in human blood and also react to the peroxidase that is present in dietary constituents such as rare red meat, cruciferous vegetables, and some fruits.53 Further, unlike gFOBT, FIT is not subject to false-negative results in the presence of high-dose vitamin C supplements, which block the peroxidase reaction. In addition, because globin is degraded by digestive enzymes in the upper gastrointestinal tract, FIT also are more specific for lower gastrointestinal bleeding, thus improving their specificity for CRC. Finally, the sample collection for some variants of FIT are less demanding of patients than gFOBT, requiring fewer samples or less direct handling of stool.
FIT—Efficacy and Test Performance. Recently, a number of new FIT have entered the market, although not all are available in the United States. Some of the new FIT have been evaluated in comparison with gFOBT in diagnostic accuracy studies with human subjects who all undergo colonoscopy to define the true presence or absence of neoplasia. Other FIT have been evaluated only on the basis of their ability to detect the presence of certain concentrations of blood in laboratory settings. No FIT has been tested in a randomized trial where the outcome of interest is CRC mortality, nor is it likely, as is the case with colonoscopy, that such a study will ever be undertaken.
A number of studies over the past 20 years have compared the diagnostic accuracy of various FIT with gFOBT (most often Hemoccult II or Hemoccult SENSA). In this review, we have focused on studies that compared different FIT with Hemoccult SENSA since at present it has the highest sensitivity of currently marketed gFOBT.49,54–58 Based on data from these 6 studies, it appears that there are no clear patterns of superior performance in overall test performance between a high-sensitivity guaiac-based test (Hemoccult SENSA) and a variety of FIT.
FIT has been performed in subjects undergoing screening colonoscopy to determine one-time sensitivity and specificity. Morikawa et al studied 21,805 asymptomatic adults who underwent testing with the Magstream 1000 test (not available in the United States), followed by colonoscopy.59 The Magstream FIT was positive in 5.6% of patients, with 27.1% sensitivity for advanced neoplasia and 65.8% sensitivity for cancer. In a similar study, although not in a totally asymptomatic population, Levi and colleagues sought to measure both sensitivity and specificity of a quantitative FIT and, as well, to measure fecal hemoglobin thresholds most predictive of advanced neoplasia and cancer.58 One thousand ambulatory patients, some with and some without symptoms of CRC, who were scheduled for colonoscopy and who were willing to also undergo an FIT with 3 samples were included in the study. The hemoglobin content of 3 bowel movements was measured. The sensitivity for cancer with 3 FIT samples with a hemoglobin threshold set at 75 ng/mL was 94.1%. Specificity for cancer was 87.5%. Allison and colleagues recently published results of a comparison of a sensitive gFOBT (Hemoccult SENSA) with a FIT (Hemoccult ICT) for cancer and advanced adenomas in the distal colon in nearly 6,000 average-risk subjects who had undergone FSIG.49 Both tests showed superior sensitivity for cancer compared with the single-test performance of an unrehydrated gFOBT. The sensitivity for CRC of the FIT and the sensitive gFOBT was 81.8% and 64.3%, respectively. However, the sensitive gFOBT showed superior performance for advanced adenomas (41.3%) compared with FIT (29.5%). Specificity of FIT tends to be higher than that observed for high-sensitivity gFOBT. For example, in the analysis by Allison et al, the specificity of Hemoccult ICT was 96.9% for distal cancer, 97.3% for distal advanced lesions, and 97.5% for all distal advanced neoplasia.49
FIT—Benefits, Limitations, and Harms. The spectrum of benefits, limitations, and harms is similar to a gFOBT with high sensitivity. One advantage of FIT over gFOBT appears to be a function of fewer demands on patients undergoing FIT compared with gFOBT. FIT does not require a restricted diet, and the sampling procedures for some forms of FIT are less demanding.60
Quality Assurance. If patients and their providers select FIT, they should be aware of several quality issues. Although there are no clinical trials assessing programmatic performance, an effective screening program will depend on repeat testing if the initial test is negative and referral for colonoscopy if the test is positive. At this time, the optimal number of FIT stool samples is not established, but 2 samples may be superior to one.61
FIT—Other Issues. Given the lack of clear difference in test performance in studies conducted to date, policy makers, providers, and patients may want to consider other factors when deciding which occult blood test to use. Relevant other factors include cost (both out-of-pocket and total costs) and likelihood of test completion, which appears to be greater with FIT compared with gFOBT.60
FIT—Conclusions and Recommendations. Annual screening with FIT that have been shown in the published, peer-reviewed literature to detect a majority of prevalent CRC in an asymptomatic population at the time of testing is an acceptable option for colorectal screening in average-risk adults aged 50 years and older. Any positive test should be followed up with colonoscopy. Adults should be informed that annual testing is necessary to achieve the fullest potential of this test and that they will need follow-up colonoscopy if test results are positive.
sDNA
Knowledge of molecular genomics provides the basis of a new method of CRC screening that tests stool for the presence of known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis. Adenoma and carcinoma cells that contain altered DNA are continuously shed into the large bowel lumen and passed in the feces. Because DNA is stable in stool, it can be differentiated and isolated from bacterial DNA found in the feces.62 No single gene mutation is present in cells shed by every adenoma or cancer. Thus, a multitarget DNA stool assay is required to achieve adequate sensitivity. At present there is only one commercially available sDNA test. The prototype assay of this test (version 1.0) for which most of the published evidence is available consisted of a multiple-marker panel that included 21 separate point mutations in the K-ras, APC, P53 genes; a probe for BAT-26 (a marker of microsatellite instability); and a marker of DNA integrity analysis (DIA). The sDNA that is currently commercially available is a second-generation version of this test (version 1.1) that includes this same marker panel but incorporates several technical advances related to processing and specimen preservation.63,64 Whereas gFOBT and FIT test a sample of stool or sample of water surrounding stool, the currently available sDNA test requires the entire stool specimen (30 g minimum to ensure an adequate sample of stool for evaluation). Collection kits have been designed to facilitate specimen collection and mailing and to enhance compliance.
sDNA—Efficacy and Test Performance. Several studies on the sensitivity and specificity of sDNA testing for CRC detection have been published utilizing a panel of DNA markers.37,65–69 Test sensitivity for CRC in these studies ranged from 52% to 91%, with specificity ranging from 93% to 97%. Lower sensitivity in some of these studies has been attributed to suboptimal sensitivity performance of DIA resulting from DNA degradation during transit of specimens to the laboratory. The changes associated with version 1.1 are reported to address these problems. One study utilizing version 1.1 has been published by Whitney et al63 reporting a sensitivity for CRC of 70%.
sDNA has been compared to a low-sensitivity gFOBT in one large, prospective study of an average-risk screening cohort. Imperiale et al conducted an investigation in a cohort of 2,507 average-risk individuals undergoing colorectal neoplasia screening by 3 modalities: sDNA using the prototype assay (version 1.0), gFOBT (nonrehydrated Hemoccult II), and colonoscopy.37 sDNA testing had statistically significantly better sensitivity for CRC compared with Hemoccult II (52% versus 13%) and for all cancers and high-grade dysplasia (40.8% versus 14.1%), with comparable specificity. In this study, sDNA was much less sensitive in the detection of all advanced adenomas (15.1%), defined as a tubular adenoma at least 1 cm in diameter, an adenoma with a villous histologic appearance, or an adenoma with high-grade dysplasia, although it still showed superior performance to the comparison gFOBT (10.7%).37 Data on program performance of sDNA screening are lacking. Information on the sensitivity and specificity of CRC and adenoma detection comes from an evaluation of results from a single test. Also, the currently available sDNA gene test—version 1.1—has not been rigorously tested in screening cohorts but based on available data can be reasonably assumed to perform as well or better than version 1.0.63 New version assays with better DNA stabilization and simplified genetic analyses may be more sensitive than version 1.0 but require testing in screening cohorts.70
sDNA—Benefits, Limitations, and Harms. The primary benefit of sDNA is that this methodology has acceptable sensitivity for CRC and is built upon the concept of detecting molecular markers associated with advanced colorectal neoplasia. It is not dependent on the detection of occult bleeding, which is intermittent and nonspecific, and it requires only a single stool collection. Further, newer versions may have better sensitivity as more is learned about markers that are common across all prevalent CRC, as well as advanced adenomas. sDNA sampling also is noninvasive and lacks physical harm. Patient and provider acceptance of this technique appears to be high, with available data indicating that sDNA is preferred over other tests by some individuals, and among others testing with sDNA, it is at least as acceptable to patients as testing with gFOBT.29,71 Berger et al reported that most individuals undergoing sDNA who completed a mailed survey reported satisfaction with the sDNA testing process, and most reported that they would repeat testing if recommended by their physician.72
A clear limitation of sDNA testing for the detection of CRC and large adenomas is that test sensitivity is based on a panel of markers that appears to identify the majority of but not all CRC. Further, it is not known what proportion of advanced adenomas is identified with the current commercial version (version 1.1) of the sDNA test. Other potential limitations that have considerable implications for cost-effectiveness are the unit cost of the current test,73 which is much higher than the other stool tests, and the frequency with which the test should be performed, which is uncertain. Currently, the test is under review by the Food and Drug Administration for 510K certification but is commercially available under the "home brew" category.
An additional issue is the clinical relevance of a positive genetic test without identification of the cause of the abnormality; this has not been studied systematically. At issue for a test that is based on molecular markers is the degree to which a positive test, with no evidence of advanced lesions upon completion of colonoscopy, is truly negative or positive for a lesion that is not yet clinically evident. Osborn and Ahlquist have highlighted the fact that inasmuch as cancers exfoliate cells and that these cells can survive the digestive process and ultimately be excreted in stool, high prevalence supracolonic aerodigestive cancers may also be detected by sDNA.74 However, at this time, the significance of a positive test result in a patient with a negative follow-up evaluation is unknown.
Quality Assurance. Individuals should be informed about the benefits and limitations of screening for CRC with sDNA, including the facts that at present the test is more sensitive for cancer than advanced adenomas, that the current panel of markers will not identify all cancers, and that a positive test will need to be followed up with colonoscopy. Individuals should also know that the rescreening interval after a negative test is uncertain. Individuals should be made aware that their stool specimen must be packaged and shipped in a customized collection kit that includes a specially designed ice pack. Patients must have access to a working freezer and allow this ice pack to freeze for at least 8 hours prior to use. If the specimen is returned without the ice pack or if there are unforeseen delays in specimen return or processing, the specimen may be rejected.
sDNA—Other Issues. Testing stool for mutated DNA and other markers poses unique challenges in shared decision making. The panel of markers that was evaluated in population studies was not sensitive for all advanced lesions and cancer, and there is uncertainty about improvements in the sensitivity of newer versions for advanced neoplasia and cancer in screening cohorts. At this time, patients will need to be informed that sDNA will detect some but not all advanced lesions and cancers. There also is uncertainty about how positive results without evidence of advanced lesions or cancer on follow up should be interpreted by patients and whether or not these patients require a different plan for ongoing surveillance.75 Additional research is necessary to resolve these questions.
As noted previously, the most informative data on the performance of sDNA is from version 1.0, which has been replaced with version 1.1; the newer version uses the same panel
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ABSTRACT
INTRODUCTION